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The Effects of Weight Loss on Neuroadrenergic Function

Primary Purpose

Obesity, Type 2 Diabetes, Metabolic Syndrome

Status

Unknown status

Phase

Not Applicable

Locations

Australia

Study Type

Interventional

Intervention

Dietary weight loss at 25% energy deficit

About this trial

This is an interventional treatment trial for Obesity focused on measuring weight loss, metabolic syndrome, sympathetic nervous system, insulin resistance, glucose tolerance

Eligibility Criteria

45 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Men and postmenopausal women (n=120), untreated, weight-stable, non-smoking, aged 45-65 years, BMI 27-45 kg/m2, will be recruited. Glucose tolerance status will be determined by a 75-g oral glucose tolerance test (OGTT), using WHO criteria (53): normal glucose tolerance, fasting plasma glucose < 7.0 mmol/L and 2-h plasma glucose < 7.8 mmol/L; IGT, fasting plasma glucose < 7.0 mmol/L and 2-h plasma glucose > 7.8 and < 11.1 mmol/L; T2D, fasting plasma glucose > 7.0 mmol/L or 2-h plasma glucose > 11.1 mmol/L. Hyper-insulinemia will be defined as an insulin area under the curve during OGTT > 8000 mU/L ∙ min-1 and hypo-insulinemia as < 8000 mU/L ∙ min-1.

Exclusion Criteria:

Prior history of cardiovascular disease (previous myocardial infarction, angina, stroke, heart failure, secondary hypertension), renal (serum creatinine >0.12 mmol/L or estimated GFR <60 ml/min/1.73 m2) or hepatic disease or diseases which may affect measured parameters (e.g. thyroid disease); severe hypertension; a history of surgical weight loss; CPAP therapy; and >4 alcoholic drinks/day. T2D individuals with moderate hyperglycemia (HbA1c >9%) will be excluded so that hypoglycaemic pharmacotherapy may be instituted (54). Participants will be sought through newspaper advertising and poster displays in primary health care centres (General Practices). Newly diagnosed T2D subjects

Sites / Locations

Baker IDI Heart & Diabetes Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Normal glucose tolerant

Impaired glucose tolerant

Type 2 diabetic hyperinsulinemic

Type 2 diabetic hypoinsulinemic

Arm Description

Weight loss attained by 25% caloric restriction. This arm will be both a glycemic and time control. Initially they will undergo a 4-month weight maintenance phase (acting as time control), followed by 4 month weight loss.

Weight loss using 25% caloric restriction. Impaired glucose tolerant subjects will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance

Weight loss using 25% caloric restriction. This group will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance

Weight loss via 25% caloric restriction. This group will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance

Outcomes

Primary Outcome Measures

Change in whole-body norepinephrine kinetics

The study will examine the dynamic processes of norepinephrine spillover into and removal from the central plasma compartment using the isotope dilution technique.Measurements will be made at baseline, after 4 months active weight loss, and again after 3 months weight loss maintenance. The weight loss maintenance phase will permit differentiation of the effects of active weight loss (incorporating both negative energy balance and weight loss per se) and stable lower body weight on sympathetic neural parameters.

Secondary Outcome Measures

Change in muscle sympathetic nerve activity

Muscle sympathetic nerve firing will be quantified by the technique of mirconeurography at baseline and after 4 months active weight loss and 3 months weight loss maintenance. The weight loss maintenance phase will permit differentiation of the effects of active weight loss (incorporating both negative energy balance and weight loss per se) and stable lower body weight on sympathetic nerve firing and pattern.

Full Information

NCT ID

NCT01771042

First Posted

January 15, 2013

Last Updated

January 16, 2013

Sponsor

Baker Heart Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT01771042

Brief Title

The Effects of Weight Loss on Neuroadrenergic Function

Official Title

Neuroadrenergic Dysfunction Along the Diabetes Continuum: Benefits of Weight Loss Within Different Strata of Metabolic Risk

Study Type

Interventional

2. Study Status

Record Verification Date

January 2013

Overall Recruitment Status

Unknown status

Study Start Date

April 2013 (undefined)

Primary Completion Date

April 2017 (Anticipated)

Study Completion Date

April 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Baker Heart Research Institute

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Elevated subconscious nervous system activity is a characteristic of the obese state and contributes importantly to the risk of heart disease and diabetes. This project will compare sympathetic nervous system activity and function in a group of obese persons with differing levels of sugar tolerance (normal, impaired and type 2 diabetic). Inter-relationships with insulin action, blood pressure, heart and kidney function will be determined before and after a 4-month weight loss and 3-month weight loss maintenance program. It is hypothesized that the transition from normal sugar tolerance to impaired sugar tolerance to type 2 diabetes will be accompanied by escalating sympathetic nervous system dysfunction. Furthermore, that weight loss will favorably improve sympathetic function, with greatest benefits occurring in those subjects who are insulin resistant with high blood insulin concentration.

Detailed Description

The twin epidemics of obesity and diabetes represent a major public health problem worldwide. There is a growing body of evidence to suggest that autonomic dysfunction, comprising elevated sympathetic nervous system (SNS) activity and blunted sympathetic neural responsiveness plays a role in both the pathogenesis and target organ complications of obesity and diabetes. The proposed project will undertake a detailed comparative analysis of neuroadrenergic function along the diabetes continuum, its inter-relationship with insulin sensitivity and secretion, and target organ function, and the benefits of active weight loss and weight loss maintenance within different strata of metabolic risk.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Obesity, Type 2 Diabetes, Metabolic Syndrome

Keywords

weight loss, metabolic syndrome, sympathetic nervous system, insulin resistance, glucose tolerance

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Normal glucose tolerant

Arm Type

Experimental

Arm Description

Arm Title

Impaired glucose tolerant

Arm Type

Experimental

Arm Description

Weight loss using 25% caloric restriction. Impaired glucose tolerant subjects will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance

Arm Title

Type 2 diabetic hyperinsulinemic

Arm Type

Experimental

Arm Description

Weight loss using 25% caloric restriction. This group will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance

Arm Title

Type 2 diabetic hypoinsulinemic

Arm Type

Experimental

Arm Description

Weight loss via 25% caloric restriction. This group will undergo 4 months weight loss (25% caloric deficit) followed by 3 months weight loss maintenance

Intervention Type

Other

Intervention Name(s)

Dietary weight loss at 25% energy deficit

Intervention Description

Dietary weight loss at 25% energy deficit. Dietary macronutrient content will comprise 25% protein, 30% fat and 45% carbohydrate.

Primary Outcome Measure Information:

Title

Change in whole-body norepinephrine kinetics

Description

Time Frame

4 months and 7 months

Secondary Outcome Measure Information:

Title

Change in muscle sympathetic nerve activity

Description

Time Frame

4 months and 7 months

Other Pre-specified Outcome Measures:

Title

Change in insulin sensitivity

Description

Insulin sensitivity will be assessed by the gold standard euglycemic hyperinsulinemic clamp method at baseline and after 4 months active weight loss and 3 months weight loss maintenance. The weight loss maintenance phase will permit differentiation of the effects of active weight loss (incorporating both negative energy balance and weight loss per se) and stable lower body weight on insulin sensitivity.

Time Frame

4 months and 7 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

45 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Men and postmenopausal women (n=120), untreated, weight-stable, non-smoking, aged 45-65 years, BMI 27-45 kg/m2, will be recruited. Glucose tolerance status will be determined by a 75-g oral glucose tolerance test (OGTT), using WHO criteria (53): normal glucose tolerance, fasting plasma glucose < 7.0 mmol/L and 2-h plasma glucose < 7.8 mmol/L; IGT, fasting plasma glucose < 7.0 mmol/L and 2-h plasma glucose > 7.8 and < 11.1 mmol/L; T2D, fasting plasma glucose > 7.0 mmol/L or 2-h plasma glucose > 11.1 mmol/L. Hyper-insulinemia will be defined as an insulin area under the curve during OGTT > 8000 mU/L ∙ min-1 and hypo-insulinemia as < 8000 mU/L ∙ min-1. Exclusion Criteria: Prior history of cardiovascular disease (previous myocardial infarction, angina, stroke, heart failure, secondary hypertension), renal (serum creatinine >0.12 mmol/L or estimated GFR <60 ml/min/1.73 m2) or hepatic disease or diseases which may affect measured parameters (e.g. thyroid disease); severe hypertension; a history of surgical weight loss; CPAP therapy; and >4 alcoholic drinks/day. T2D individuals with moderate hyperglycemia (HbA1c >9%) will be excluded so that hypoglycaemic pharmacotherapy may be instituted (54). Participants will be sought through newspaper advertising and poster displays in primary health care centres (General Practices). Newly diagnosed T2D subjects

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Dr Nora E Straznicky, PhD MPH

Phone

61 3 8532 1371

nora.straznicky@bakeridi.edu.au

First Name & Middle Initial & Last Name or Official Title & Degree

Ms Mariee T Grima, BNutr MDiet

Phone

61 3 8532 1523

mariee.grima@bakeridi.edu.au

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Dr Nora E Straznicky, PhD MPH

Organizational Affiliation

Baker IDI Heart & Diabetes Institute

Official's Role

Principal Investigator

Facility Information:

Facility Name

Baker IDI Heart & Diabetes Institute

City

Melbourne

State/Province

Victoria

ZIP/Postal Code

8008

Country

Australia

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Nora E Straznicky, PhD MPH

Phone

61 3 8532 1371

nora.straznicky@bakeridi.edu.au

First Name & Middle Initial & Last Name & Degree

Nora E Straznicky, PhD MPH

12. IPD Sharing Statement

Citations:

PubMed Identifier

26297500

Citation

Straznicky NE, Grima MT, Sari CI, Lambert EA, Phillips SE, Eikelis N, Kobayashi D, Hering D, Mariani JA, Dixon JB, Nestel PJ, Karapanagiotidis S, Schlaich MP, Lambert GW. Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss. Cardiovasc Diabetol. 2015 Aug 22;14:113. doi: 10.1186/s12933-015-0276-2.

Results Reference

derived

PubMed Identifier

25590214

Citation

Straznicky NE, Grima MT, Lambert EA, Sari CI, Eikelis N, Nestel PJ, Phillips SE, Hering D, Karapanagiotidis S, Dixon JB, Schlaich MP, Lambert GW. Arterial norepinephrine concentration is inversely and independently associated with insulin clearance in obese individuals with metabolic syndrome. J Clin Endocrinol Metab. 2015 Apr;100(4):1544-50. doi: 10.1210/jc.2014-3796. Epub 2015 Jan 15.

Results Reference

derived

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The Effects of Weight Loss on Neuroadrenergic Function

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